Rational targeting of cooperating layers of the epigenome yields enhanced therapeutic efficacy against AML Academic Article uri icon

Overview

MeSH Major

  • Anthracyclines
  • Chromatin Assembly and Disassembly
  • DNA (Cytosine-5-)-Methyltransferase
  • Drug Resistance, Neoplasm
  • Leukemia, Myeloid, Acute

abstract

  • ©2019 American Association for Cancer Research. Disruption of epigenetic regulation is a hallmark of acute myeloid leukemia (AML), but epigenetic therapy is complicated by the complexity of the epigenome. Herein, we developed a long-term primary AML ex vivo platform to determine whether targeting different epigenetic layers with 5-azacytidine and LSD1 inhibitors would yield improved efficacy. This combination was most effective in TET2mut AML, where it extinguished leukemia stem cells and particularly induced genes with both LSD1-bound enhancers and cytosine-methylated promoters. Functional studies indicated that derepression of genes such as GATA2 contributes to drug efficacy. Mechanistically, combination therapy increased enhancer–promoter looping and chromatin-activating marks at the GATA2 mut locus. CRISPRi of the LSD1-bound enhancer in patient-derived TET2 AML was associated with dampening of therapeutic GATA2 induction. TET2 knockdown in human hematopoietic stem/progenitor cells induced loss of enhancer 5-hydroxymethylation and facilitated LSD1-mediated enhancer inactivation. Our data provide a basis for rational targeting of cooperating aberrant promoter and enhancer epigenetic marks driven by mutant epigenetic modifiers. SIGNIFICANCE: Somatic mutations of genes encoding epigenetic modifiers are a hallmark of AML and potentially disrupt many components of the epigenome. Our study targets two different epigenetic layers at promoters and enhancers that cooperate to aberrant gene silencing, downstream of the actions of a mutant epigenetic regulator.

publication date

  • July 2019

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC6606333

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-19-0106

PubMed ID

  • 31076479

Additional Document Info

start page

  • 872

end page

  • 889

volume

  • 9

number

  • 7